The road less traveled: Developing pharmacist clinician-scientists through divergent training pathways.

PURPOSE: Professional organizations have emphasized the growing need for pharmacists to possess advanced research skills; however, there is a scarcity of training programs aimed at nurturing clinician-scientists. This report outlines 3 critical care-focused research programs, each offering a unique approach to training clinician-scientists. SUMMARY: Limited resources and formalized programs are available to bridge the gap between the demand for and availability of skilled clinician-scientists. Several programs have stepped forward to share their experiences in establishing and executing training initiatives aimed at cultivating skilled clinician-scientists in the critical care practice space. CONCLUSION: Enhancing the development of clinician-scientists for clinical and translational research is necessary in the critical care clinical pharmacy community.

Characterizing redundancy in pharmacy residency research projects.

PURPOSE: Each year, roughly 5,000 residents conduct research on clinical and practice-based topics to meet the requirements of the ASHP residency standards related to research and project management. Several investigators have evaluated residency research project publication rates, but redundancy among projects has not been evaluated. The primary objective of this study was to determine the rate of redundancy among pharmacy residency research projects. METHODS: This was a retrospective cohort analysis of abstracts accepted to various regional pharmacy residency conferences from 2017 through 2020. Each abstract was placed in a pharmacy domain by therapeutic area. The categorized data for each year were then further evaluated to identify clinical categories for the year. Topics were labeled as redundant if at least 10 projects fell into the same focus area within a clinical category. Descriptive statistics were used to quantify the incidence of redundancy each year. RESULTS: A total of 4,027 abstracts were included. The most common pharmacy domains were infectious disease, internal medicine, and benefit of pharmacy services. Overall, 8.2% projects (332 of 4,027) were categorized as redundant. The most common focus areas were rapid diagnostics, opioid reduction protocols, and vancomycin area-under-the-curve vs trough monitoring. CONCLUSION: Pharmacy residency research projects encompassed topics across a wide range of pharmacotherapy areas. Approximately 1 in 12 projects was redundant. This is likely because the project addressed a "hot topic" in practice and may represent an opportunity for institutions to collaborate to optimize project efficiency and impact.

Publication of pharmacy resident research projects: A systematic review and meta-analysis.

PURPOSE: Pharmacy residents often aspire to develop research skills through conducting a research project. Project publication rates among pharmacy residents are variable and at times low; however, previous studies have been limited to specific geographic regions and timeframes. This study sought to conduct a systematic review and meta-analysis to determine the proportion of pharmacy resident research projects published in the peer-reviewed literature. METHODS: A systematic review of PubMed MEDLINE, Embase, and the Web of Science Core Collection was performed from database inception to May 25, 2023. Articles were included if they were full-text, peer-reviewed manuscripts of original research presenting observational data regarding pharmacy resident research project publication rates. Data extraction and assessment of risk of bias were conducted by 2 independent reviewers. A proportional meta-analysis using a random effects model of the included studies was conducted to generate a pooled, overall proportion. RESULTS: The search yielded 5,225 records and 12 articles that met the inclusion criteria. All studies were retrospective and observational. Risk of selection and cohort identification biases was "high," whereas that of detection and timeframe biases was "low." The included studies represented 6,990 resident research projects, 777 of which were published in the peer-reviewed literature. Publication rates across individual studies ranged from 1.8% to 36.2%. The pooled proportion (scale of 0 to 1) of projects published was 0.13 (95% CI, 0.09-0.19). CONCLUSION: Pharmacy resident research project publication rates are low at 13%. Furthermore, studies reporting project publication rates over time suggest a neutral or negative trend in publication rates despite an exponential increase in the number of pharmacy residents.

Enhanced renal clearance impacts levetiracetam concentrations in patients with traumatic brain injury with and without augmented renal clearance.

BACKGROUND: The purpose of this study was to examine the impact of ARC on levetiracetam concentrations during the first week following acute TBI. The hypothesis was levetiracetam concentrations are significantly lower in TBI patients with augmented renal clearance (ARC) compared to those with normal renal clearance. METHODS: This is a prospective cohort pharmacokinetic study of adults with moderate to severe TBI treated with levetiracetam during the first week after injury. Serial blood collections were performed daily for analysis of levetiracetam, cystatin C, and 12-hr creatinine clearance (CrCl) determinations. Patients were divided into two cohorts: with (CrCl ≥130 ml/min/1.73 m2) and without ARC. RESULTS: Twenty-two patients with moderate to severe TBI were included. The population consisted primarily of young male patients with severe TBI (mean age 40 years old, 68% male, median admission GCS 4). Each received levetiracetam 1000 mg IV every 12 h for the study period. ARC was present in 77.3% of patients, with significantly lower levetiracetam concentrations in ARC patients and below the conservative therapeutic range (< 6mcg/mL) for all study days. In patients without ARC, the serum concentrations were also below the expected range on all but two study days (Days 4 and 5). Four of the 22 (18.2%) patients exhibited seizure activity during the study period (two of these patients exhibited ARC). Cystatin C concentrations were significantly lower in patients with ARC, though the mean for all patients was within the typical normal range. CONCLUSIONS: ARC has a high prevalence in patients with moderate to severe TBI. Levetiracetam concentrations after standard dosing were low in all TBI patients, but significantly lower in patients with ARC. This study highlights the need to consider personalized drug dosing in TBI patients irrespective of the presence of ARC. CLINICAL TRIAL REGISTRATION: This study was registered at cliicaltrials.gov (NCT02437838) Registered on 08/05/2015, https://clinicaltrials.gov/ct2/show/NCT02437838 .

Multicenter Comparison of the Safety and Efficacy of Clopidogrel Versus Ticagrelor for Neuroendovascular Stents.

BACKGROUND: Dual antiplatelet therapy (DAPT) is commonly employed for neuroendovascular stenting due to the significant risk of thromboembolism. Clopidogrel and aspirin are most often selected as initial DAPTs; however, there is limited literature available to support guidance of DAPT in this setting. The objective of this study was to evaluate safety and efficacy in patients whose final regimen included either DAPT with aspirin and clopidogrel (DAPT-C) or DAPT with aspirin and ticagrelor (DAPT-T). METHODS: This was a multicenter, retrospective cohort of patients who underwent neuroendovascular stenting and received DAPT between July 1, 2017, and October 31, 2020. Study participants were allocated into groups based on discharge DAPT regimen. The primary outcome was incidence of stent thrombosis at 3-6 months on DAPT-C versus DAPT-T, as defined by the presence of thrombus on imaging or new onset stroke. Secondary outcomes included major and minor bleeding and death within 3-6 months after the procedure. RESULTS: Five hundred and seventy patients were screened across 12 sites. Of those, 486 were included (DAPT-C n = 360, DAPT-T n = 126). There was no difference in the primary outcome of stent thrombosis between the DAPT-C and DAPT-T groups (8% vs. 8%, p = 0.97) and no difference in any of the secondary safety outcomes. CONCLUSIONS: Using DAPT-C or DAPT-T regimens in a broad population of neuroendovascular stenting procedures appears to have similar safety and efficacy profiles. Further prospective evaluation is warranted to streamline the practice of DAPT selection and monitoring to determine the impact on clinical outcomes.

Multicenter comparison of antiplatelet treatment strategies for urgent/emergent neuroendovascular stenting.

BACKGROUND: Emergent neuroendovascular stenting presents challenges for the utilization of antiplatelet agents. METHODS: This was a multicenter, retrospective cohort of patients who underwent emergent neuroendovascular stenting. The primary endpoints were thrombotic and bleeding events in relation to the timing of antiplatelet administration, route of administration, and choice of intravenous (IV) agent and the study investigated practice variability in antiplatelet utilization. RESULTS: Five-hundred and seventy patients were screened across 12 sites. Of those, 167 were included for data analysis. For patients who presented with ischemic stroke, artery dissection and emergent internal carotid artery (ICA) stenting who received an antiplatelet agent prior to or during the procedure, 57% were given an IV antiplatelet agent; for patients who were given an antiplatelet agent after the procedure, 96% were given an oral agent. For patients who presented for aneurysm repair and received an antiplatelet agent prior to or during the procedure, 74% were given an IV agent; patients who were given an antiplatelet agent after the completion of the procedure were given an oral antiplatelet agent 90% of the time. In patients who presented with ischemic stroke, artery dissection and emergent ICA stenting who received oral antiplatelet agents post-procedure were more likely to have thrombotic events compared to those who received oral antiplatelet agents prior to or during the procedure (29% vs 9%; p = 0.04). There were no differences in the primary outcomes observed when comparing other antiplatelet treatment strategies. CONCLUSION: The optimal timing of antiplatelet administration in relation to stent placement and route of administration of antiplatelet agents is unclear. Timing and route of administration of antiplatelet agents may have an effect on thrombosis in emergent neuroendovascular stenting. Significant practice variation exists in antiplatelet agent utilization in emergent neuroendovascular stenting.

Personalized antiseizure medication therapy in critically ill adult patients.

Precision medicine has the potential to have a significant impact on both drug development and patient care. It is crucial to not only provide prompt effective antiseizure treatment for critically ill patients after seizures start but also have a proactive mindset and concentrate on epileptogenesis and the underlying cause of the seizures or seizure disorders. Critical illness presents different treatment issues compared with the ambulatory population, which makes it challenging to choose the best antiseizure medications and to administer them at the right time and at the right dose. Since there is a paucity of information available on antiseizure medication dosing in critically ill patients, therapeutic drug monitoring is a useful tool for defining each patient's personal therapeutic range and assisting clinicians in decision-making. Use of pharmacogenomic information relating to pharmacokinetics, hepatic metabolism, and seizure etiology may improve safety and efficacy by individualizing therapy. Studies evaluating the clinical implementation of pharmacogenomic information at the point-of-care and identification of biomarkers are also needed. These studies may make it possible to avoid adverse drug reactions, maximize drug efficacy, reduce drug-drug interactions, and optimize medications for each individual patient. This review will discuss the available literature and provide future insights on precision medicine use with antiseizure therapy in critically ill adult patients.

Comparison of nimodipine formulations and administration techniques via enteral feeding tubes in patients with aneurysmal subarachnoid hemorrhage: A multicenter retrospective cohort study.

BACKGROUND: Nimodipine improves outcomes following aneurysmal subarachnoid hemorrhage (aSAH) and current guidelines suggest that patients with aSAH receive nimodipine for 21 days. Patients with no difficulty swallowing will swallow the whole capsules or tablets; otherwise, nimodipine liquid must be drawn from capsules, tablets need to be crushed, or the commercially available liquid product be used to facilitate administration through an enteral feeding tube (FT). It is not clear whether these techniques are equivalent. The goal of the study was to determine if different nimodipine formulations and administration techniques were associated with the safety and effectiveness of nimodipine in aSAH. METHODS: This was a retrospective multicenter observational cohort study conducted in 21 hospitals across North America. Patients admitted with aSAH and received nimodipine by FT for ≥3 days were included. Patient demographics, disease severity, nimodipine administration, and study outcomes were collected. Safety end points included the prevalence of diarrhea and nimodipine dose reduction or discontinuation secondary to blood pressure reduction. Predictors of the study outcomes were analyzed using regression modeling. RESULTS: A total of 727 patients were included. Administration of nimodipine liquid product was independently associated with higher prevalence of diarrhea compared to other administration techniques/formulations (Odds ratio [OR] 2.28, 95% confidence interval [CI] 1.41-3.67, p-value = 0.001, OR 2.76, 95% CI 1.37-5.55, p-value = 0.005, for old and new commercially available formulations, respectively). Bedside withdrawal of liquid from nimodipine capsules prior to administration was significantly associated with higher prevalence of nimodipine dose reduction or discontinuation secondary to hypotension (OR 2.82, 95% CI 1.57-5.06, p-value = 0.001). Tablet crushing and bedside withdrawal of liquid from capsules prior to administration were associated with increased odds of delayed cerebral ischemia (OR 6.66, 95% CI 3.48-12.74, p-value <0.0001 and OR 3.92, 95% CI 2.05-7.52, p-value <0.0001, respectively). CONCLUSIONS: Our findings suggest that enteral nimodipine formulations and administration techniques might not be equivalent. This could be attributed to excipient differences, inconsistency and inaccuracy in medication administration, and altered nimodipine bioavailability. Further studies are needed.

Hypertonic saline use in neurocritical care for treating cerebral edema: A review of optimal formulation, dosing, safety, administration and storage.

PURPOSE: Current Neurocritical Care Society guidelines on the management of cerebral edema recommend hypertonic saline (HTS) over mannitol in some scenarios, but practical questions remain regarding the appropriate administration method, concentration/dose, monitoring to ensure safe use, and storage. The aim of this article is to address these practical concerns based on the evidence currently available. SUMMARY: Many different hypertonic solutions have been studied to define the optimal hyperosmolar substance to relieve acute cerebral edema in patients with conditions such as acute ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, and traumatic brain injury. Mannitol and HTS are the main hyperosmolar therapies in use in contemporary neurocritical care practice. Contemporary use of HTS has followed a circuitous path in regards to the practical aspects of dosing and formulation, with evidence mainly consisting of retrospective or observational data. The effectiveness of bolus doses of HTS to lower acutely elevated intracranial pressure is well accepted. Adverse events with use of HTS are often mild and non-clinically significant if appropriate monitoring of serum sodium and chloride concentrations is performed. Available evidence shows that peripheral administration of HTS is likely safe in certain circumstances. Timely utilization of HTS is complicated by regulatory requirements for safe storage, but with appropriate safeguards HTS can be stored in patient care areas. CONCLUSION: HTS formulations, methods of administration, infusion rate, and storage vary by institution, and no practice standards exist. Central intravenous administration may be preferred for HTS, but peripheral intravenous administration is safe provided measures are undertaken to detect and prevent phlebitis and extravasation. The safe use of HTS is possible with proper protocols, education, and institutional safeguards in place.

Efficacy and safety of vancomycin loading doses in critically ill patients with methicillin-resistant Staphylococcus aureus infection.

BACKGROUND: While vancomycin loading doses may facilitate earlier pharmacokinetic-pharmacodynamic target attainment, the impact of loading doses on clinical outcomes remains understudied. Critically ill patients are at highest risk of morbidity and mortality from methicillin resistant Staphylococcus aureus (MRSA) infection and hypothesized to most likely benefit from a loading dose. We sought to determine the association between receipt of a vancomycin loading dose and clinical outcomes in a cohort of critically ill adults. METHODS: Four hundred and forty-nine critically ill patients with MRSA cultures isolated from blood or respiratory specimens were eligible for the study. Cohorts were established by receipt of a loading dose (⩾20 mg/kg actual body weight) or not. The primary outcome was clinical failure, a composite outcome of death within 30 days of first MRSA culture, blood cultures positive ⩾7 days, white blood cell count up to 5 days from vancomycin initiation, temperature up to 5 days from vancomycin initiation, or substitution (or addition) of another MRSA agent. RESULTS: There was no difference in the percentage of patients experiencing clinical failure between the loading dose and no loading dose groups (74.8% versus 72.8%; p = 0.698). Secondary outcomes were also similar between groups, including mortality and acute kidney injury, as was subgroup analysis based on site of infection. Exploratory analyses, including assessment of loading dose based on quartiles and a multivariable logistic regression model showed no differences. CONCLUSION: Use of vancomycin loading doses was not associated with improved clinical outcomes in critically ill patients with MRSA infection.

Identifying errors and safety considerations in patients undergoing thrombolysis for acute ischemic stroke.

BACKGROUND & PURPOSE: Alteplase is the standard of care for early pharmacologic thrombolysis after acute ischemic stroke (AIS). Alteplase is also considered a high-alert medication and is fraught with potential for error. We sought to describe the difference in medication error rates in in patients receiving alteplase for acute ischemic stroke from regional hospitals compared to patients receiving alteplase at the Comprehensive Stroke Center. METHODS: This was a retrospective cohort comparison of patients who were greater than 18 years old that received intravenous alteplase for the treatment of AIS from June 2015 to June 2018. Several institution specific databases were utilized to obtain pertinent data. A standardized taxonomy was utilized to classify medication errors. Patients were excluded if they received any fibrinolytic other than alteplase or if alteplase was used for a non-stroke indication. Two cohorts (from regional hospitals or the Comprehensive Stroke Center (CSC)) were compared. RESULTS: A total of 676 patients received alteplase during the study period (34% from the CSC and 66% from regional hospitals). There were 133 (19.8%) errors identified. Ten errors (1.6%) occurred at the CSC and 123 (18.2%) errors occurred at regional hospitals. More patients who had an error with alteplase administration (12.7%) experienced a hemorrhagic conversion compared to those with no error in administration (7.2%, p= 0.04). CONCLUSION: The error rate of alteplase infusion for ischemic stroke is high, particularly in patients from referring centers. Errors may be associated with adverse events. Further education and administration safeguards should be implemented to decrease the risk of medication errors.

Levetiracetam Compared to Phenobarbital as a First Line Therapy for Neonatal Seizures: An Unexpected Influence of Benzodiazepines on Seizure Response.

OBJECTIVES: Neonatal seizures are common complications. Phenobarbital is the agent of choice but leads to adverse neurologic outcomes. There has been increased use of newer agents like levetiracetam. The objective of this study was determining the rate of seizure resolution in neonates treated with phenobarbital or levetiracetam. METHODS: This was a retrospective, single-center, cohort study from June 1, 2012-June 1, 2018 evaluating seizure resolution in neonates following first-line treatment with phenobarbital versus levetiracetam. Data were collected via review of the patient's charts in the electronic medical record. The primary outcome was seizure resolution without addition of a second antiepileptic agent. Logistic regression was used to assess the impact of pertinent variables. RESULTS: Each group included 73 patients. The mean gestational age was 36.01 and 37.91 weeks for the phenobarbital and levetiracetam groups, respectively (p = 0.011). The phenobarbital group had higher rates of intraventricular hemorrhage at baseline. The median birth weight was 2750 and 3002 grams in the phenobarbital and levetiracetam groups, respectively (p = 0.10). Forty-five neonates (61.6%) achieved seizure resolution with phenobarbital compared with 30 neonates (41.1%) with levetiracetam (p = 0.01). In neonates who did not receive a benzodiazepine, seizure resolution was similar between groups (51-52%). In neonates who received a benzodiazepine, seizure resolution rate was 94.1% (16/17 neonates) for phenobarbital and 18.2% (4/22 neonates) for levetiracetam. CONCLUSIONS: These findings suggest seizure resolution with levetiracetam, and phenobarbital may be impacted by benzodiazepine administration. If no benzodiazepine is used, these agents demonstrated similar efficacy. Further research into the pharmacodynamic interaction with benzodiazepines is necessary.

Stress-Related Gastrointestinal Bleeding in Patients with Aneurysmal Subarachnoid Hemorrhage: A Multicenter Retrospective Observational Study.

BACKGROUND/OBJECTIVE: Stress-related mucosal bleeding (SRMB) occurs in approximately 2-4% of critically ill patients. Patients with aneurysmal subarachnoid hemorrhage (aSAH) have a (diffuse) space-occupying lesion, are critically ill, often require mechanical ventilation, and frequently receive anticoagulation or antiplatelet therapy after aneurysm embolization, all of which may be risk factors for SRMB. However, no studies have evaluated SRMB in patients with aSAH. Aims of the study were to determine the incidence of SRMB in aSAH patients, evaluate the effect of acid suppression on SRMB, and identify specific risk factors for SRMB. METHODS: This was a multicenter, retrospective, observational study conducted across 17 centers. Each center reviewed up to 50 of the most recent cases of aSAH. Patients with length of stay (LOS) < 48 h or active GI bleeding on admission were excluded. Variables related to demographics, aSAH severity, gastrointestinal (GI) bleeding, provision of SRMB prophylaxis, adverse events, intensive care unit (ICU), and hospital LOS were collected for the first 21 days of admission or until hospital discharge, whichever came first. Descriptive statistics were used to analyze the data. A multivariate logistic regression modeling was utilized to examine the relationship between specific risk factors and the incidence of clinically important GI bleeding in patients with aSAH. RESULTS: A total of 627 patients were included. The overall incidence of clinically important GI bleeding was 4.9%. Of the patients with clinically important GI bleeding, 19 (61%) received pharmacologic prophylaxis prior to evidence of GI bleeding, while 12 (39%) were not on pharmacologic prophylaxis at the onset of GI bleeding. Patients who received an acid suppressant agent were less likely to experience GI bleeding than patients who did not receive pharmacologic prophylaxis prior to evidence of bleeding (OR 0.39, 95% CI 0.18-0.83). The multivariate regression analysis identified any instance of elevated intracranial pressure, creatinine clearance < 60 ml/min and the incidence of cerebral vasospasm as specific risk factors associated with GI bleeding. Cerebral vasospasm has not previously been described as a risk for GI bleeding (OR 2.5 95% CI 1.09-5.79). CONCLUSIONS: Clinically important GI bleeding occurred in 4.9% of patients with aSAH, similar to the general critical care population. Risk factors associated with GI bleeding were prolonged mechanical ventilation (> 48 h), creatinine clearance < 60 ml/min, presence of coagulopathy, elevation of intracranial pressure, and cerebral vasospasm. Further prospective research is needed to confirm this observation within this patient population.

Alcohol Withdrawal Syndrome in Neurocritical Care Unit: Assessment and Treatment Challenges.

Alcohol withdrawal syndrome (AWS) can range from mild jittery movements, nausea, sweating to more severe symptoms such as seizure and death. Severe AWS can worsen cognitive function, increase hospital length of stay, and in-hospital mortality and morbidity. Due to a lack of reliable history of present illness in many patients with neurological injury as well as similarities in clinical presentation of AWS and some commonly encountered neurological syndromes, the true incidence of AWS in neurocritical care patients remains unknown. This review discusses challenges in the assessment and treatment of AWS in patients with neurological injury, including the utility of different scoring systems such as the Clinical Institute Withdrawal Assessment and the Minnesota Detoxification Scale as well as the reliability of admission alcohol levels in predicting AWS. Treatment strategies such as symptom-based versus fixed dose benzodiazepine therapy and alternative agents such as baclofen, carbamazepine, dexmedetomidine, gabapentin, phenobarbital, ketamine, propofol, and valproic acid are also discussed. Finally, a treatment algorithm considering the neurocritical care patient is proposed to help guide therapy in this setting.

First-Dose Vancomycin Pharmacokinetics Versus Empiric Dosing on Area-Under-the-Curve Target Attainment in Critically Ill Patients.

BACKGROUND: Early attainment of target area under the curve (AUC) to minimum inhibitory concentration (MIC) ratios have been associated with clinical success, as well as lower incidence of acute kidney injury (AKI), in patients receiving vancomycin for methicillin-resistant Staphylococcus aureus (MRSA). Critically ill patients are particularly vulnerable to poor outcomes from infection and face multiple risk factors for AKI, thus early precision dosing of vancomycin is vital in this population. We hypothesized that a personalized dosing approach, using vancomycin levels obtained after the first dose to guide further dosing, would be superior to empiric dosing in terms of AUC target attainment assessed at steady state (SS). METHODS: A retrospective cohort study of 66 critically ill adult patients admitted to the medical intensive care unit without AKI and receiving vancomycin with at least two SS concentrations obtained for AUC calculation was performed. Patients were separated into cohorts based on whether they had two concentrations assessed after the first dose of vancomycin and were subsequently dosed based on personalized pharmacokinetic calculations (first-dose kinetics) or whether they were empirically dosed using population estimates. The primary outcome was AUC target attainment (400-600 mg hour/L) at SS. RESULTS: Compared with patients receiving empiric dosing by population estimates, using first-dose kinetics to guide subsequent dosing resulted in significantly greater AUC target attainment at SS (58.6% first-dose vs 32.4% empiric; p=0.033). Patients dosed empirically yielded more variable AUC values across a wide range compared with the first-dose kinetics group (coefficient of variation 40.7% empiric vs 26.1% first-dose). There was no difference in AKI up to 48 hours after SS concentrations between the two dosing schemes. CONCLUSIONS: A dosing strategy using two vancomycin serum concentrations after the first dose and calculating personalized pharmacokinetic parameters to guide subsequent dosing is associated with greater AUC target attainment at SS compared with empiric dosing of vancomycin in critically ill adults with relatively stable renal function.